Pharmacological profile of T-1032, a novel specific phosphodiesterase type5 inhibitor, in isolated rat aorta and rabbit corpus cavernosum

This study was designed to examine the pharmacological properties of T-1032 (methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pysidinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)-3-isoquinoline carboxy late sulfate), a novel phosphodi esterase type 5 inhibitor, in isolated rat aorta and rabbit corpus cavernos um. T-1032 (3 x 10(-11) to 3 x 10(-7) M) caused an endothelium-dependent re laxation in the isolated rat aorta precontracted with phenylephrine. and th e relaxation was accompanied by an increase in cGMP but not cAMP levels. Th e T-1032-induced relaxation was attenuated by NG-nitro-L-arginine methyl es ter (L-NAME) (10(-3) M), a nitric oxide (NO) synthase inhibitor. or 1H-[1,2 .4]oxadiazolo[4,3-alpha ]quinoxalin-1-one (ODQ) (10(-5) M), a guanylyl cycl ase inhibitor. T-1032 (10(-9), 10(-8) M) produced a potentiation of the rel axation induced by sodium nitroprusside, but not of the relaxation induced by isoproterenol. In the isolated rabbit corpus cavernosum precontracted wi th phenylephrine. the electrical field stimulation-induced relaxation was a ttenuated by treatment with tetrodotoxin(10(-6) M) as well as L-NAME(10(-4) M). The L-NAME-inhibited relaxation was restored by treatment with L-argin ine (5 x 10(-4) M). T-1032 (10(-9) to 10(-6) M) and sildenafil (10(-9) to 1 0(-6) M) produced a potentiation of the electrical field stimulation-induce d relaxation as well as a decrease in basal tension in a concentration-depe ndent manner. It was concluded that T-1032 had potentiating effects on the NO/cGMP signaling pathway in isolated tissues. probably through specific bl ockade of phosphodiesterase type 5. T-1032 would be a useful compound to ex amine the physiologic functions of phosphodiesterase type 5 in mammalian ti ssues. (C) 2001 Elsevier Science B.V. All rights reserved.